THE REGULATION OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS) BY ADENOSINE IN MYOCARDIAL ISCHEMIA-REPERFUSION

腺苷在心肌缺血再灌注中对中性粒细胞胞外陷阱（NETS）的调节

基本信息

批准号：
10242718
负责人：
Rebecca Diane Levit
金额：
$ 44.35万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242718
关键词：
5&apos -Nucleotidase ADORA2A gene Adenosine Adenosine A2 Receptors Adult Respiratory Distress Syndrome Alginates Animal Model Anti-Inflammatory Agents Atherosclerosis Autoimmune Diseases Automobile Driving Blood Platelets Bone Marrow Cardiovascular Diseases Cell Transplantation Cells Chromatin Coagulation Process Crohn&apos s disease Cyclic AMP Cytoplasmic Granules DNA Data Deaminase Deep Vein Thrombosis Diffuse Dose Encapsulated Endothelial Cells Equilibrium Extracellular Matrix Extracellular Space Functional disorder Future Heart Histone H1 Histones Hour Human Immune In Vitro Infection Inflammation Inflammatory Inflammatory Response Innate Immune System Interruption Knockout Mice Leukocytes Light Link Lymphocyte Mediating Mediator of activation protein Metabolism Molecular Conformation Morbidity - disease rate Multiple Sclerosis Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocarditis Myocardium Necrosis Pathway interactions Pharmacology Physiological Physiological Processes Play Pre-Eclampsia Process Production Protein-arginine deiminase Purinergic P1 Receptors Reactive Inhibition Reactive Oxygen Species Regulation Reperfusion Injury Reperfusion Therapy Rheumatoid Arthritis Rodent Model Role Septic Shock Signal Pathway Signal Transduction Site Sterility Stimulus Surface Techniques Testing Therapeutic Thrombin Thrombosis Tissues Transplantation White Blood Cell Count procedure acute coronary syndrome antimicrobial autoimmune pathogenesis cost efficacy evaluation efficacy testing experimental study extracellular feasibility testing heart function hemodynamics in vivo inflammatory milieu inhibitor/antagonist macrophage mesenchymal stromal cell migration mortality myocardial damage neutrophil novel novel therapeutic intervention nucleoside triphosphate pathogen prevent targeted treatment treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Reperfusion of the ischemic heart is lifesaving in myocardial infarction, but the physiologic processes triggered by reperfusion can cause subsequent damage. The innate immune system plays a prominent role in reperfusion injury. Neutrophils release multiple toxic mediators and the appreciation of the role of neutrophil extracellular traps (NETs) in MI/R pathophysiology is gaining importance. Adenosine is known to mitigate many pro-inflammatory immune processes while ATP released from dying and necrotic cells, activates immune cells. ATP is metabolized to adenosine by ectonucleotidases expressed on many cells including mesenchymal stromal cells (MSCs). MSCs are known to highly express ecto-nucleoside triphosphate diphosphohydrolase-1 (NTDPase1, CD39) and ecto-5’-nucleotidase (CD73). Modulation of purinergic metabolism may be a powerful mechanism used by MSCs to inhibit inflammation in their native bone marrow as well as when transplanted for therapeutic purpose. Currently little is known about endogenous regulation of NET production and we have hypothesize that adenosine may be a key endogenous regulator. Our preliminary data shows that MSC transplanted to the heart encapsulated in alginate can modulate the innate inflammatory response to MI/R. Furthermore, encapsulated MSCs increase myocardial adenosine levels, reduce reactive oxygen species, and decrease the number of leukocytes and neutrophils in the heart after 24 hours. We will use human neutrophils as well as neutrophils isolated from mice lacking key adenosine receptors to understand the role of adenosine signaling in MI/R. We will also use a rodent model of MI/R to test our novel NET-regulatory strategy in vivo. The results of these studies will identify new therapeutic strategies for treatment of innate immune MI/R injury. It is our aims to 1) delineate the importance of adenosine receptor 2A (A2A) signaling in the regulation of NET formation; 2) evaluate the intracellular signaling pathways involved in NET regulation; 3) test the feasibility of MSC modulation of purinergic metabolism to prevent NETs in MI/R.

项目概要/摘要缺血心脏的再灌注可以挽救心肌梗塞的生命，但生理过程再灌注引发的损伤可导致先天免疫系统在其中发挥重要作用。再灌注损伤中性粒细胞释放多种毒性介质和中性粒细胞的升值作用。细胞外陷阱 (NET) 在 MI/R 病理生理学中变得越来越重要，众所周知，腺苷可以缓解许多症状。促炎性免疫过程，而死亡和坏死细胞释放的 ATP 会激活免疫细胞。 ATP 通过许多细胞（包括间充质细胞）上表达的核酸酶代谢为腺苷已知基质细胞 (MSC) 高度表达外核苷三磷酸二磷酸水解酶-1。 (NTDPase1、CD39) 和 5'-核苷酸酶 (CD73) 调节嘌呤能代谢可能是一种强大的作用。间充质干细胞用于抑制其天然骨髓中的炎症以及移植后的炎症的机制治疗目的。目前，人们对 NET 生产的内源性调控知之甚少，但我们已经掌握了这一点我们的初步数据表明，腺苷可能是MSC移植到的关键内源性调节剂。藻酸盐封装的心脏可以调节对 MI/R 的先天炎症反应。封装的 MSC 增加心肌腺苷水平，减少活性氧，并降低 24小时后心脏中的白细胞和中性粒细胞的数量我们将使用人类中性粒细胞。从缺乏关键腺苷受体的小鼠中分离出中性粒细胞，以了解腺苷信号传导的作用在 MI/R 中，我们还将使用 MI/R 的啮齿动物模型来测试我们的新型 NET 调节策略的体内结果。这些研究将确定治疗先天免疫 MI/R 损伤的新治疗策略。我们的目标是 1) 阐明腺苷受体 2A (A2A) 信号传导在调节 NET形成；2）评估参与NET调节的细胞内信号通路；3）测试可行性 MSC 调节嘌呤能代谢以预防 MI/R 中的 NET。